Double-Blind
Authors: Kathleen G. Julian
Journal: Annals of Internal Medicine (2022)

On Being a DoctorNovember 2022Double-BlindFREEKathleen G. Julian, MDKathleen G. Julian, MDDivision of Infectious Diseases, Penn State Health Milton S. Hershey Medical Center, Hershey, PennsylvaniaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-2461 Audio Reading - “Double-Blind” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Double-Blind” by Kathleen G. Julian, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail “As long as the QTC is carefully monitored, you can maximize the dose of hydroxychloroquine,” I told the COVID-19 ICU physician over the phone, acting as if I knew what I was talking about. Which, of course, I did not.Hydroxychloroquine for COVID-19—remember? That was March 2020. On the first day that I carried the COVID-19 pager, calls were frequent and frenzied. As an infectious diseases physician, I found myself advising on this drug that I had never prescribed before. Although we knew supporting data were weak, hydroxychloroquine was the only “treatment” available for COVID-19. We needed something.How, in this darkness, did we ever begin to find our way?Now, a couple of years later and in a different frame of mind, we tend to forget where we were. We also tend to forget what it took to inch therapies forward, in some semblance of order, when SARS-CoV-2 invaded every hospital.At ICU stations, other haphazard drugs came up in clinical discussions about COVID-19. For a patient reeling against hypoxia and hypotension (who was already receiving high-dose hydroxychloroquine), a young resident asked me, “What about trying … ?” I don't recall the name of the drug the resident suggested, as meaningless as they seemed. Azithromycin? Lopinavir–ritonavir? Or drugs that tampered with the immune system, sounding potent because of their danger and audacity? All I remember was the manner in which the resident asked—wishing to do anything except watch this woman die.We were desperate for treatment data we could trust.Then, just as SARS-CoV-2 gathered into its first full storm and forced the closure of all other research at our hospital, into this vacuum came the possibility of participation in an RCT for the treatment of COVID-19. Compared with the chaotic try-this or try-that approach, an RCT was entirely different. This was law and order. There were criteria to meet, protocols to follow, events to report. Of note, data would be collected and carefully tracked; these were ways to make sense within mayhem.Although medical advances have long relied on high-quality RCTs, in 2020, these studies seemed to take on further significance. The most rigorous RCTs offered something to trust and, surprisingly, something to believe in—for both clinician–investigators and patients.For our group of clinician–investigators, it began like this: On an afternoon in April 2020, I listened intently alongside my infectious diseases colleague while the NIH study director sketched the protocol for ACTT (Adaptive COVID-19 Treatment Trial), the first in a series of double-blind, placebo-controlled RCTs for the treatment of COVID-19. After our earlier failures to gain access to experimental antiviral programs, my colleague had taken a long shot and requested that our hospital be an ACTT study site. The drug to be tested had already been quietly studied in other coronaviruses long before the current pandemic. This unfamiliar antiviral remdesivir was as alluring at that time as it is commonplace now.During that first call, we took many notes while the NIH study director described the data to be collected, the blood needed, the IRB approvals to be sought. So focused were we on access to remdesivir through participation in this RCT that we were not intimidated by the long lists of tasks.However, one statement did stand out: “We're running low on placebo,” the NIH director said solemnly. We nodded, maintaining the formality of the meeting. Yet, as soon as the call ended and we sensed that the NIH might select our hospital, we allowed ourselves to joke, “Don't bother about placebo—just send remdesivir!”A few days later, I heard that our hospital was, indeed, accepted into ACTT and study doses were on their way. This seemed to be the first sign of anything good among all the hours working long into the night, the deaths in Italy, the swelling of cases in nearby New York, the threat of becoming seriously ill from work. When, alone at my desk, I read the e-mail confirming the arrival of study drugs on our hospital premises, I was momentarily overcome by both fatigue and relief. Because I needed to, I already believed in this antiviral. Of course, no investigator starts a study without hope—why else put forth the enormous effort?By this time, placebo had also been found. In an example of duality, we embraced the importance of controls and accepted that half of the doses would be nothing but saline. We also accepted that we would never know which was which. The best clinical trials, double-blind and placebo-controlled, are structured around this recognition: Researchers, no matter how brilliant, are human and prone to see more hope than what the stark, blinded numbers will permit. Less well-designed studies, including those on hydroxychloroquine, had led us astray.As for patients, the first person with COVID-19 whom I enrolled in ACTT was just under my age, a man with rheumatoid arthritis taking rituximab. He was receiving only 4 L of oxygen. Yet, if he tried to get out of bed, his oxygen saturation quickly dropped. I “met” him through the glass wall of the ICU. He returned my wave. In the surreal state of speaking to my patient not in person but by phone, I prepared to go over a 15-page consent form.I asked, “Do you want me to call your wife so she can listen with you?”“No,” he said calmly. “You can talk to me. My family doesn't know everything.” He'd been traveling overseas; upon his return, worsening dyspnea had forced him to come directly to our hospital. Visitors were not allowed. “They cannot see me, so I don't want them to know about the ICU part.”As we talked, I realized that there were many reasons why this trial had to be blind, why I should not know whether he was receiving remdesivir or placebo. I had always thought blinding was the best way to collect data that have subjective components. What I hadn't appreciated was that blinding also relieved both of us of the burden of knowing, much less choosing, which “treatment” would be assigned. Although I had made it clear in the consent process that we did not know whether the drug would work, I unequivocally wanted this patient to have remdesivir. To see him receive placebo would have been demoralizing.Another time, I had to go back to a 61-year-old woman who was already enrolled in ACTT and receiving infusions in order to review an updated consent form and request her signature. The task seemed irritably bureaucratic, and I did not know how she would react. However, sparing me, she interrupted my explanations and said, “Just let me sign it now. I don't mind.”In contrast, another man with COVID-19 in the ICU spoke sternly after receiving the consent form: “Let me tell you right now—I'm not going to sign this until my lawyer reads it.” I had not dealt with this type of curve ball. There was no time to make special arrangements. Then, despite the large-bore tubes of oxygen buckled to his nose, he broke out in a laugh and added, “Good thing I am a lawyer! And will be my own lawyer!” In no time, he signed the papers.While we carefully go through many pages of consent forms, ultimately, people who agree to participate in studies cannot assimilate the details. It all comes down to trust. This isn't uncommon in a hospital; however, in the context of a voluntary trial, this trust was made manifest.I close with this last story of when, in quietly spoken words, I felt the delicate weight of lives held by ACTT. A family had been deliberating on behalf of their father, an 80-year-old man with COVID-19 pneumonia. Weakened, he had to rely on his daughter for decision making. It was obvious as we met via a three-way phone call that she had weighed this decision carefully, hoping that the medications could bring him back. He seemed lost, occasionally coughing and sputtering as he held onto the phone.At the end of my review of the long consent document, his daughter prepared to give formal permission on his behalf. She turned to speak to her father through the phone. “Daddy,” she said, “we've talked it over—Mom and I. And we think the study is a good idea.”He could not muster a word.“Daddy,” she then said in a way that moved my objective heart, “even if it is placebo, we know you would have wanted to help.”In ways like these, thousands more entrusted themselves to ACTT. These RCTs, implemented with speed, dexterity, and scientific rigor, had pressed forward through both stepwise advances and strikeout setbacks. Two and a half years later, the public tone of the pandemic has shifted. ACTT has closed. Although serious COVID-19 remains dangerous and difficult to manage, a range of data-backed treatments is available.Now I recognize that in the beginning, desperate for data we could trust, these collaborative RCTs shined a light forward—even though the strength that drove these trials was itself blind in many ways. As for the many human “subjects,” we should remember how they, knowing we did not know but still reading our hope, had agreed to long consent forms and experimental drugs. For clinician–investigators, RCTs, even with their risk for failure, embody beliefs that inspire—belief in the truth within high-quality controlled studies and belief that out there, somewhere, better therapies can be found. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Division of Infectious Diseases, Penn State Health Milton S. Hershey Medical Center, Hershey, PennsylvaniaCorresponding Author: Kathleen G. Julian, MD, Division of Infectious Diseases, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; e-mail, [email protected]psu.edu.This article was published at Annals.org on 27 September 2022. PreviousarticleNextarticle Advertisement Audio Reading - “Double-Blind” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Double-Blind” by Kathleen G. Julian, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics November 2022Volume 175, Issue 11Page: 1617-1618 ePublished: 27 September 2022 Issue Published: November 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...